EP0555283A1 - Zwischenprodukte für die herstellung von 4,5-difluoroanthranilsäure. - Google Patents

Zwischenprodukte für die herstellung von 4,5-difluoroanthranilsäure.

Info

Publication number
EP0555283A1
EP0555283A1 EP91918730A EP91918730A EP0555283A1 EP 0555283 A1 EP0555283 A1 EP 0555283A1 EP 91918730 A EP91918730 A EP 91918730A EP 91918730 A EP91918730 A EP 91918730A EP 0555283 A1 EP0555283 A1 EP 0555283A1
Authority
EP
European Patent Office
Prior art keywords
compound
formula
base
reacting
alkali metal
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP91918730A
Other languages
English (en)
French (fr)
Other versions
EP0555283B1 (de
Inventor
Tamim F Braish
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Pfizer Inc
Original Assignee
Pfizer Inc
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Filing date
Publication date
Application filed by Pfizer Inc filed Critical Pfizer Inc
Publication of EP0555283A1 publication Critical patent/EP0555283A1/de
Application granted granted Critical
Publication of EP0555283B1 publication Critical patent/EP0555283B1/de
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
    • C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
    • C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
    • C07C259/10—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to carbon atoms of six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/87—Benzo [c] furans; Hydrogenated benzo [c] furans
    • C07D307/89—Benzo [c] furans; Hydrogenated benzo [c] furans with two oxygen atoms directly attached in positions 1 and 3

Definitions

  • the present invention relates to compounds which are intermediates in the preparation of 4,5-difluoroanthranilic acid, an intermediate itself in the synthesis of quinolone antibacterials, and methods of preparing these intermediates.
  • United States Patent No. 4,833,270 also relates to the synthesis of 4,5-difluoroanthranilic acid by, first, reacting 3,4-difluoroaniline with hydroxylamine hydrochloride in the presence of chloral. The resulting intermediate is then cyclyzed using sulfuric acid to form 5,6-difluoroisatin. The 4,5-difluoroanthranilic acid is produced by oxidation of the aforementioned isatin with hydrogen peroxide. As before, however, 3,4-difluoroaniline is expensive and difficult to obtain.
  • United States Patent Nos. 4,374,266 and 4,374,267 show a multi-step conversion process of 4,5-dichlorophthalic anhydride to 4,5-difluoroanthranilic acid.
  • the processes are complex and involves the use of multiple reaction vessels.
  • R 1 is 0- X+
  • X is NH 3 0H, an alkali metal, or an alkaline earth metal (such as K, Na, Li, Cs, or Ca)
  • R 2 is NHOH or R 1 and R* taken together to form the group
  • N-OH The present invention also relates to a method of preparing a compound of formula I wherein R 1 and R 2 are attached to the group s N-OH
  • the present invention also relates to a method of preparing a compound of the formula
  • SUBSTI and X is as defined for formula I with an alkyl or a.ryl sulfonyl chloride and excess base.
  • the present invention also relates to a method of preparing the compound of formula II in one reaction vessel comprising reacting the compound of the formula
  • 4,5-dichloro phthalic acid (1) available from the Aldrich Chemical Co. is converted to the corresponding anhydride (2) by heating (1) to between about 100°C and about 150°C, preferably 138°C, under an inert atmosphere with a dialkyl anhydride, such as trifluoroacetic anhydride or acetic anhydride, or acetyl chloride, preferably the latter, in an inert solvent such as toluene or benzene, preferably toluene.
  • a halogen-halogen exchange is performed on the 4,5-dichlorophthalic anhydride (2) to produce a 4,5- difluoro substituted version thereof (3) in solution.
  • SUBSTITUTESHEET reaction consists of reacting the dichloro compound (2) with an alkali metal fluoride such as NaF, KF, or CsF, preferably
  • the ratio of fluoride to anhydride should be from about 2.5:1 to about 20:1, preferably 3:1.
  • the halogen-halogen exchange is run at a temperature of between about 150°C and about 220°C, preferably 185°C.
  • the solvent used should be an aprotic solvent such as dimethylformamide, sulfolane, or dimethylsulfoxide, preferably sulfolane, at concentrations of from about 3.5:1 to about 10:1, preferably 4:1.
  • the reaction can be run either in a pressure vessel or at atmospheric pressure.
  • the product in the solution is isolated as the corresponding diacid (4) by reacting the solution with water and a caustic base, such as sodium hydroxide or potassium hydroxide.
  • the organic layer is then removed and the water layer acidified to form the diacid
  • the 4,5-difluorophthalic acid (4) is converted to the corresponding anhydride (5) using the same procedure as was described previously for converting acid (1) to anhydride
  • the anhydride ring is opened to produce the corresponding benzoate (6) by reacting (5) with from about 2 equivalents to about 3 equivalents of neutral hydroxylamine, preferably
  • the reaction is carried out in base such as sodium methoxide or potassium hydroxide, preferably the latter, and can be carried out at a temperature at between about 0°C and about 45°C, preferably room temperature, (about 27°C) .
  • base such as sodium methoxide or potassium hydroxide, preferably the latter, and can be carried out at a temperature at between about 0°C and about 45°C, preferably room temperature, (about 27°C) .
  • the benzoate (6) can be converted to 4,5- difluoroanthranilic acid (9) by two routes.
  • the first route involves treating the benzoate (6) with an alkyl or aryl sulfonyl chloride (about 2 to 3 equivalents, preferably 2 equivalents) and excess base (about 3:5 to 10 equivalents, preferably 4 equivalents) .
  • bases such as alkali metal or alkaline earth metal hydroxide-type bases include NaOH,
  • Benzoate (6) is converted to metal benzoate intermediate (7) with cation X+ varying depending on the hydroxide-type base used. The process continues and metal benzoate intermediate (7) is converted to the difluoroanthranilic acid (9) .
  • p-Toluenesulfonyl chloride is the preferred sulfonate because of its crystallinity and ease of handling.
  • the reaction can be conducted at between about -10°C and about 50°C, preferably room temperature (about 27°C) .
  • the second route involves converting the benzoate (6) to N-hydroxy-4,5-difluorophthalamide (8).
  • the imide (8) is then converted to the 4,5-difluoroanthranilic acid through the same reaction as was described above for converting the benzoate (7) to the desired acid (8) using the akyl or aryl sulfonyl chloride and excess hydroxide-type base.
  • the 4,5-difluoroanthranilic acid (9) is converted to 2- chloro-4,5-difluoro benzoic acid (10) via diazatization with an alkyl nitrate or an inorganic nitrite.
  • alkyl nitrates include isoamylnitrate and t-butyl nitrate, preferably the latter.
  • an organic polar solvent should be used, such as dimethoxy ethane or acetonitrile, preferably the latter.
  • an inorganic nitrite such as sodium nitrite
  • water is the preferred solvent.
  • Copper should also be used in either the organic or inorganic reaction solution. Copper (II) chloride, copper oxide, or copper bronze in hydrochloric acid can be used preferably copper (II) chloride.
  • the 2-chloro-4,5-difluorobenzoic acid can be converted into the aforementioned antibacterial compounds using
  • the antibacterial compounds may be administered alone in an admixture with a pharmaceutical carrier.
  • a pharmaceutical carrier should be selected with regard to the intended route of administration and standard pharmaceutical practice.
  • Such antibacterial compounds can be administered orally or in the form of tablets containing such excipients as starch or lactose, or in capsules either alone or in an admixture with excipients, or in the form of elixirs or suspensions containing flavoring or coloring agents.
  • animals are advantageously contained in an animal feed or drinking water in a concentration of 5 to 5000 ppm, preferably 25 to 500 ppm. They can also be injected parenterally, for example, intramuscularly, intravenously or subcutaneously.
  • the antibacterial compounds can be administered to animals intramuscularly or, subcutaneously at dosage levels of about 0.1 to 50 mg/kg/day, advantageously 0.2 to 10 mg/kg/day given in a single daily dose or up to 3 divided doses.
  • the antibacterial compounds can be administered to humans for the treatment of bacterial diseases by either the oral or parenteral routes, and may be administered orally at dosage levels of from about 0.1 to 500 mg/kg/day, advantageously 0.5 to 50 mg/kg/day given in a single dose or up to 3 divided doses.
  • dosage levels are from about 0.1 to 200 mg/kg/day, advantageously 0.5 to 50 mg/kg/day. While intramuscularly administration may be a single dose or up to 3 divided doses, intravenous administration can include a continuous drip. Variations will necessarily occur depending on the weight and condition of the subject being treated and the particular route of administration chosen as will be known to those -skilled in the art.
  • the antibacterial activity of the compounds is shown by testing according to the Steer's replicator technique which is a standard _in vitro bacterial testing method described by E. Steers et al., Antibiotics and Chemotherapy, 9. 307 (1959). The present invention is illustrated by the following Examples, but in no way is it intended to be limited thereby.
  • Example 1 4.5-dichlorophthalic anhydride (2) 200 g of 4,5-dichlorophthalic acid (851 mmol, M.W. 235) was suspended in 480 ml of acetic anhydride and the solution was heated to reflux for 5 hours. The solution was allowed to cool to room temperature over 2 hours, then cooled to 0°C and filtered and washed with 100 ml of hexane and dried to provide the title compound with a 92% yield (170 g) . M.P. 184°C - 186°C. l H NMR(CDCI 3 ) : 8.1 (s)
  • Example 2 4.5-Difluorophthalic acid (4.
  • the title compound of Example 1 (50g, 230 mmol) was suspended in 200 ml of sulfolane and potassium fluoride (46.9 g, 810 mmol) was added and the solution was heated to 185°C for 3 hours.
  • IN NaOH solution was added to bring the solution to pH 14, and the solution was extracted with 4X100 ml of diethylether.
  • the pH was then adjusted to 2.5 with 10% acqueous HCl and the solution was extracted with 4X75 ml of ethylacetate.
  • the combined organic layers were dried over MgS0 and evaporated to give 41.1 g or the title compound (81% yield).
  • H NMR(CDCI 3 ) 7.86 (t) .
  • Combustion analysis for C 8 H 4 F 2 0 4 C, 47.54; H, 1.99. Found: C, 47.21; H, 2.01.
  • Example 2 The title compound of Example 2 (28.2 g, 139.5 mmol) was suspended in 90 ml of acetic anhydride and heated to reflux for 2 hours. The reaction was evaporated to dryness to give
  • Example 4 Hvdroxylamine-2-hydroxamic acid-4,5-difluorobenzoate (6) Hydroxyl amine hydrochloride (19.24 g, 276.9 mmol) was added to sodium methoxide in methanol (6.37 g of Na metal in 250 ml of methanol) , and heated gently to 45°C over a period of 45 minutes. The reaction was then filtered and the filtrate was cooled to 0°C and the title compound of Example 3 (17 g, 92.3 mmol) was added. The reaction was then allowed to warm to room temperature and stirred for 1 hour. The product was isolated via filtration and drying of the solids in vacuo to provide 17.5 g of the title compound (78% yield). M.P. 242- 245°C (discoloration at 140°C) , l K NMR(d ⁇ -DMSO) : 7.52 (q) ; 7.74(q).
  • Example 5 4.5-difluoroanthranilic acid .9.
  • To the title compound of Example 4 300 g, 1.19 mmol was added 5 ml of 10% NaOH solution and p-toluenesulfonyl chloride (0.5 g, 2.38 mmol) and the mixture was allowed to stir for 16 hours.
  • the reaction was acidified to pH 4.5 with 10% HCl and the reaction was extracted with 3X20 ml of methylene chloride.
  • the combined organic layers were dried over MgS0 4 and evaporated to give 176 mg of the title compound (85% yield).
  • M.P. 178-180°C. ! H NMR(d ⁇ -DMSO) 6.72 (q) ; 7.60 (q) .
  • Example 7 The title compound of Example 7 (100 mg, 0.5 mmol) was suspended in 5 ml of 10% NaOH solution and p-toluenesulfonyl chloride (105 mg, 0.55 mmol) was added and the solution was allowed to stir for 16 hours. The pH of the reaction solution was then adjusted to 4.5 with 10% HCl and the title compound was extracted with 3X25 ml of methylene chloride. The combined organic layers were dried over MgS0 4 and evaporated to give 60 mg of the title compound (69% yield) . M.P. 178-180°C. X H NMR(d-DMSO) : 6.72 (q) ; 7.60 (q) .

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Sewage (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Cosmetics (AREA)
  • Indole Compounds (AREA)
  • Quinoline Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
EP91918730A 1990-10-31 1991-07-29 Zwischenprodukte für die herstellung von 4,5-difluoroanthranilsäure Expired - Lifetime EP0555283B1 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US60666690A 1990-10-31 1990-10-31
US606666 1990-10-31
PCT/US1991/005171 WO1992007822A1 (en) 1990-10-31 1991-07-29 Intermediates in the preparation of 4,5-difluoroanthranilic acid

Publications (2)

Publication Number Publication Date
EP0555283A1 true EP0555283A1 (de) 1993-08-18
EP0555283B1 EP0555283B1 (de) 1995-04-05

Family

ID=24428951

Family Applications (1)

Application Number Title Priority Date Filing Date
EP91918730A Expired - Lifetime EP0555283B1 (de) 1990-10-31 1991-07-29 Zwischenprodukte für die herstellung von 4,5-difluoroanthranilsäure

Country Status (13)

Country Link
US (1) US5436368A (de)
EP (1) EP0555283B1 (de)
JP (1) JP2552412B2 (de)
AT (1) ATE120729T1 (de)
CA (1) CA2091569C (de)
DE (1) DE69108737T2 (de)
DK (1) DK0555283T3 (de)
ES (1) ES2070517T3 (de)
FI (1) FI931938A0 (de)
GR (1) GR3015725T3 (de)
IE (1) IE65215B1 (de)
PT (1) PT99378B (de)
WO (1) WO1992007822A1 (de)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113444021A (zh) * 2020-03-25 2021-09-28 深圳有为技术控股集团有限公司 邻胺基芳香酸的异羟肟酸重排法制备

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE130302C (de) *
DE136788C (de) *
CA1181420A (en) * 1980-12-29 1985-01-22 Michael J. Fifolt Method for the preparation of fluoroanthranilic compounds
CA1169078A (en) * 1980-12-29 1984-06-12 Michael J. Fifolt Method for the preparation of fluorophthalamic compounds
US4954639A (en) * 1989-08-28 1990-09-04 Occidental Chemical Corporation Single pot process for making a fluoroanthranilic acid

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9207822A1 *

Also Published As

Publication number Publication date
EP0555283B1 (de) 1995-04-05
IE65215B1 (en) 1995-10-04
PT99378A (pt) 1992-09-30
DK0555283T3 (da) 1995-07-03
FI931938A (fi) 1993-04-29
JP2552412B2 (ja) 1996-11-13
GR3015725T3 (en) 1995-07-31
ATE120729T1 (de) 1995-04-15
ES2070517T3 (es) 1995-06-01
DE69108737T2 (de) 1995-08-17
FI931938A0 (fi) 1993-04-29
IE913783A1 (en) 1992-05-22
WO1992007822A1 (en) 1992-05-14
CA2091569C (en) 1997-02-18
CA2091569A1 (en) 1992-05-01
PT99378B (pt) 1999-04-30
DE69108737D1 (de) 1995-05-11
JPH05507287A (ja) 1993-10-21
US5436368A (en) 1995-07-25

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